Fabrication of biocleavable crosslinked polyprodrug vesicles via reversible donor–acceptor interactions for enhanced anticancer drug delivery

Incorporation of various dynamic stimuli-responsive bonds to nanocarriers has been repeatedly highlighted to provide an elegant solution to the tradeoff between extracellular stability and intracellular high therapeutic efficiency; however, most of the developed systems still suffer from drug leakage-associated side effects due to insufficient stability and unsatisfactory therapeutic efficiency attributed to low drug loading capacity. To further address these critical issues, herein we reported a coordination-driven formation of biocleavable crosslinked polyprodrug vesicles (CPV) based on the reversible coordination interactions between the electron acceptor-containing polyprodrug and electron donor-based crosslinker, 1,6-hexanediamine. The resulting CPV exhibited a high drug loading content of 34.8%, and simultaneously enhanced extracellular micelle stability and promoted intracellular redox-triggered decrosslinking and drug release. More importantly, a comparison study further revealed that the CPV outperformed the noncrosslinked analogues in terms of greater stability, faster redox-triggered decrosslinking and drug release, a more compact structure with a smaller size toward higher cellular uptake, and greater in vitro cytotoxicity. This work thus developed a robust reversible crosslinking strategy to address high stability vs. sufficient therapeutic efficiency dilemma of polyprodrug-based nanocarriers.